Nerve injury or disease often leads to intractable neuropathic pain. Axons which are severed undergo Wallerian degeneration. This involves the activation of Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells and the release of inflammatory cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins and alter ion channel function. This evokes spontaneous activity in primary afferent neurons that is crucial for the onset and maintenance of pain. In addition, secondary mediators such as colony stimulating factor 1 are generated and released from primary afferent terminals. These promote release of tertiary mediators such as brain-derived neurotrophic factor and interleukin 1b from spinal microglia and astrocytes. Tertiary mediators facilitate the generation and transmission of nociceptive information by facilitating excitatory transmission and attenuating inhibitory transmission in the dorsal horn. Transfer of information between neurons and immune cells is bidirectional. Neurons directly control immune cell function in a process termed neurogenic neuroinflammation. Increased permeability of the blood-brain barrier allows access of immune cells to neurons in central pain pathways. This, together with neurogenic neuroinflammation, increases activity throughout the pain sensory system. This review provides an overview of processes involved in the generation and persistence of peripherally generated neuropathic pain. Attention is drawn to the idea that pain etiology is dependent on the nature of the injury and different processes operate in males compared to females.
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